How HIV Makes Immune Cells Commit Suicide
Lead author Arik Cooper and colleagues from the National Institute for Allergy and Infectious Diseases, which is part of the National Institutes of Health, write about their findings in the 5th June online issue of Nature.
HIV has infected more than 60 million and killed neary 30 million people around the world. Every day in an infected person the HIV destroys billions of infection-fighting CD4+ T cells, until the immune system is no longer able to regenerate or fight other infections.
The virus does this in several ways. One way is by killing cells directly: it hijacks cells and uses their resources to make copies of itself. These copies emerge as buds that burst through the cell membrane, killing the cell in the process. Another way HIV kills the host cell directly is just by exhausting its resources.
And another way that causes host cells to die, is when the host cell machinery becomes grossly distorted from being used to make virus copies, this can trigger a process known as programmed cell death or apoptosis.
This study reveals the underlying mechanisms of that process.
When HIV enters the host cell, it starts reprogramming its protein-building machinery by inserting its own genes into the cellular DNA.
Cooper and colleages discovered that during this insertion step, a cellular enzyme called DNA-dependent protein kinase (DNA-PK) becomes active. The enzyme normally helps repair double-stranded breaks in molecules that make up DNA.
But when HIV integrates its genes into host cell DNA, this results in single-stranded breaks at the insertion points.
To their surprise, Cooper and colleagues found that the DNA breaks occuring during HIV integration activates DNA-PK, which then performs an unusually destructive role: it triggers a signal that causes apoptosis in the CD4+ T cell.
"We propose that activation of DNA-PK during viral integration has a central role in CD4+ T-cell depletion, raising the possibility that integrase inhibitors and interventions directed towards DNA-PK may improve T-cell survival and immune function in infected individuals."
In other words, it may be possible to treat HIV-infected people in the early stages of infection by giving them drugs that block those early steps in virus replication that occur up to and including DNA-PK activation.
And not only might this stop the virus being able to copy itself, but it could also preserve enough CD4+ T cells to keep the immune system able to fight infection.
The researchers also suggest the findings help to explain the formation of reservoirs of resting HIV-infected cells, and give clues as to how to eliminate them.
In another study published recently in Nature, describes how another team of researchers in the US has for the first time, with the help of a supercomputer, cracked the chemical structure of the capsid or protein shell of HIV.
Written by Catharine Paddock PhD